The present disclosure relates generally to modulating inflammation using progesterone metabolites. More particularly, the present disclosure relates the use of two progesterone metabolites, 6β-hydroxyprogesterone (6β-OHP) and 16α-hydroxyprogesterone (16α-OHP), for mitigating inflammation in various tissue types in the body. In one particularly suitable embodiment, the metabolites modulate uterine contractility in patients with localized uterine inflammation/infection. In another suitable embodiment, the metabolites mitigate systemic inflammation though their effects on monocytes and macrophage differentiation/function.
Inflammation is a process by which tissues respond to various insults. It is characterized by upregulation of chemokines, cytokines, and pattern recognition receptors that sense microbes and tissue breakdown products. During pregnancy, the balance of Th1 (cell-mediated immunity) and Th2 (humoral immunity) cytokines is characterized by an initial prevalence of Th2 cytokines, followed by a progressive shift toward Th1 predominance late in gestation, that, when is abnormal, may initiate and intensify the cascade of inflammatory cytokine production involved in adverse pregnancy outcomes. Maternal and placental hormones may affect the inflammatory pathway. Hypoxia and the innate immune response are 2 adaptive mechanisms by which organisms respond to perturbation in organ function, playing a major role in spontaneous abortion, intrauterine growth restriction, preeclampsia, and preterm delivery.
Preterm labor is defined as the presence of uterine contractions of sufficient frequency and intensity (also referred to herein as contractile force) to effect progressive effacement and dilation of the cervix prior to term gestation. Occurring at 20-37 weeks' gestation, preterm labor precedes almost half of preterm births in the United States. More particularly, preterm birth is a major public health problem with approximately 1 in 9 babies born prematurely, leading to increased rates of infant morbidity and mortality. Preterm labors remain unexplained and the rate of preterm delivery remains unchanged at about 5%. Despite the widespread use of tocolytic drugs, there has not been any documented decrease in the rate of preterm birth in recent years. This is largely due to the fact that there is still a very limited understanding of the physiology of parturition and causes of preterm labor. Although the etiology of preterm birth is multifactorial, the mechanisms underlying inflammation associated uterine contractility are a common theme.
Progesterone, a major steroid hormone that is naturally produced by the body and which levels increase during pregnancy, and its analogues are the primary therapeutic options for the prevention of preterm birth. Investigations of 17-hydroxyprogesterone caproate (17-OHPC) have demonstrated efficacy in the prevention of recurrent preterm birth in singleton pregnancies. Further, micronized progesterone has been proposed to decrease the rates of preterm birth and neonatal morbidity in pregnant women with shortened cervical length. The mechanisms underlying the decreased rate of preterm birth are not well elucidated. Further, while it is known that progesterone is primarily metabolized by cytochrome P450 3A (CYP3A) into two metabolites, 6β-hydroxyprogesterone (6β-OHP) and 16α-hydroxyprogesterone (16α-OHP), the physiologic role of progesterone metabolism and actions of endogenous metabolites have not been well studied.
Based on the foregoing, there is a need in the art to better understand preterm labor and means for predicting and modulating preterm labor. It would be further advantageous if methods could be used on a genomic level to modulate inflammation in other tissues of a subject.
While the disclosure is susceptible to various modifications and alternative forms, specific embodiments thereof have been shown by way of example in the drawings and are herein described below in detail. It should be understood, however, that the description of specific embodiments is not intended to limit the disclosure to cover all modifications, equivalents and alternatives falling within the spirit and scope of the disclosure as defined by the appended claims.